To test the hypothesis: the mode of action of benralizumab being ADCC will target both resident and inflammatoryeosinophils whereas mepolizumab only targets inflammatory eosinophils. This will achieved by a head-to-headcomparison of the presence of…
ID
Source
Brief title
Condition
- Allergic conditions
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Number of eosinophils per high power field in rectal biopsies
Secondary outcome
1. Number of eosinophils in the peripheral blood (million/ml)
2. Kinetics of eosinophils in tissue and blood.
Background summary
Overall rationale: the production of eosinophils in the bone marrow is not
dependent on IL-5, but reactive eosinophilia
is. The prevailing idea is that eosinophil progenitors are formed independently
of IL-5 but the cells express the IL-5R
(IL-5 KO mice have terminally differentiated eosinophils in the peripheral
blood). When IL-5 is produced during T2
inflammation this cytokine acts as growth/proliferation factor for these
IL-5R-positive cells. This implicates that anti-IL-5
therapy can only act on reactive eosinophilia.
The situation with benralizumab is different. This antibody is directed against
IL-5R and kills these cells by antibodydependent
cellular cytotoxicity (ADCC). This implicates that benralizumab kills all IL-5R
positive cells (eosinophils and basophils)(1).
The recent study and review by Mesnil et al (2) again shows the presence of
resident eosinophils in homeostasis in
healthy tissues as well as in the lung. Following the above-mentioned reasoning
these cells are likely not sensitive for
IL-5 targeted therapy whereas they are sensitive for benralizumab therapy.
Conus et al. (3) supports this hypothesis as
treatment with mepolizumab does not affect eosinophil numbers in duodenal
mucosa. In addition, the expected
depletion of eosinophils in the gut tissue by benralizumab has been recently
demonstrated in patients with HES (4,5).
Study objective
To test the hypothesis: the mode of action of benralizumab being ADCC will
target both resident and inflammatory
eosinophils whereas mepolizumab only targets inflammatory eosinophils. This
will achieved by a head-to-head
comparison of the presence of (healthy) resident eosinophils in the rectal
(gut) tissue.
Study design
Investigation part 1: comparative study between 20 patients treated with
mepolizumab (Nucala) and 20 patients treated
with benralizumab (Fasenra).
Investigation part 2: longitudinal cross over study with 12 (2x6) biological
naïve patients that either start with
mepolizumab and cross after 6 months to benralizumab or vice versa
Study burden and risks
Burden is limited:
Cross-sectional study (part 1):
Three visits: 1 initiation visit (1 hr), 1 day in UMCU (glucose labeling), 1
visit for taking biopsies/2 hr
Total: 6-26 days depending on the length of the labeling: 16 hrs in total
Clinical samples: 4 small rectal biopsies, 1 tube of NaHep blood and 6 finger
pricks
Prospective cross-over study (part 2)
Four visits: 1 initiation visit (1 hr), 3 visits for taking biopsies/2 hr and
10 short visits for determination of weight and
blood differentiation
Total: 4 visits in 52 weeks: 25 hrs in total
Clinical samples: 4 small rectal biopsies, 3x1 tube of NaHep blood and 3x1
urine sample
There are very small risks associated with
1. Venipuncture: potential small leakage of blood, bruise
2. Rectal biopsy: potential small leakage of blood
3. 2H-gluocse: no known side effects at doses used in this investigation
4. Treatment with Nucala en Farenza: mild complaints such as head ache, colds,
low fever.
Heidelberglaan 100
UTRECHT 3584CX
NL
Heidelberglaan 100
UTRECHT 3584CX
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18
• Diagnosis of severe refractory eosinophilic asthma
• Eligible for mepolizumab or benralizumab therapy according the national
recommendations for severe asthma of the Dutch society for lung diseases and
tuberculosis (NVALT guideline 2013): Patients with asthma, forwhom alternative
diagnoses are excluded, comorbidity optimally treated, provoking factors
minimized and therapy compliance optimized, but despite this still have
insufficient asthma control (>= 1.5 ACQ-7 or other questionnaire) or frequent
(>=2 annually) severe exacerbations (systemic CS needed) while routinely using
highdose asthma medication (>= 1000 mcg/day fluticasone propionate equivalent
and/or daily OCS in combination with LABA or other controller medication); or
patients who can achieve asthma control only with systemic CS and are therefore
are risk for adverse effects or the corticosteroids.
• Treated with mepolizumab or benralizumab for at least 4 months.
• Before treatment with biologics a blood eosinophilia (>= 150
eosinophils/microl blood) irrespective of steroid use
Inclusion criteria healthy controls
• Age >= 18 and matching age and sex of the population of asthma patients
Exclusion criteria
• Any infection (eg. HIV, Hepatitis, STDs)
• Insulin dependent diabetes
• Smoking at present or in the last 12 months and/or a past history of more
than 10 pack years
• Proven allergic bronchopulmonary aspergillosis
• Auto-immune diseases
• Use of medication, excluding:
o Anticonceptives
o Pain killers, if used on average less than once a week
o acetylsalicylic acid 0-2 days before the start of the study
• exuberant alcohol consumption (for males > 36 glasses per week, for females
>24 glasses per week)
• Drug use
• History of cancer
• Use of biologicals other than mepolizumab or benralizumab
• daily oral steroid therapy during the three months preceding inclusion
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004676-18-NL |
| CCMO | NL74748.041.20 |